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2005 Grant - Savonenko

APP-Dependent and Independent Effects of BACE-1 Knockout on Cognition

Alena Savonenko, Ph.D.Johns Hopkins University School of MedicineBaltimore, Maryland

2005 Investigator-Initiated Research Grant

Beta-amyloid is a protein fragment suspected of disrupting cell-to-cell communication and damaging cells in Alzheimer's disease. Beta-amyloid is clipped in a two-stage process from a molecule called amyloid precursor protein (APP). The first cut is made by a protein called the beta APP cleaving enzyme 1, or BACE1.

One therapeutic strategy under investigation to block beta-amyloid production is the use of a BACE1-inhibiting drug. However, it is not known whether BACE1 has other essential roles in neuron function. Determining the whole range of BACE1 activities is important for determining what kind of side effects a BACE1-inhibiting drug may cause.

Alena Savonenko, Ph.D., and colleagues have studied genetically altered mice that have the BACE1 gene "switched off." They have observed that these mice do not have any developmental abnormalities or brain pathologies. But these mice exhibit deficits in certain types of memory and have abnormally low levels of anxiety. These findings suggest that they BACE1 may perform some function in memory and emotional processes.

In the current investigation, Dr. Savonenko's group will crossbreed BACE1-deficient mice with other genetically altered mice that carry either (1) the normal human APP gene, (2) an Alzheimer-associated APP gene, (3) another human gene associated with Alzheimer's, or (4) some combination of these genes. The various combinations will enable the researchers to tease out details about the relevance of BACE1 in normal memory, emotions and Alzheimer-related memory impairment. The findings from this work may provide valuable information about the potential efficacy and safety of a BACE1-inhibiting Alzheimer treatment.